Cardiovascular and Metabolic Risk ORIGINAL ARTICLE

Dysglycemia and a History of Reproductive Risk Factors

1 2,4 SARAH D. MCDONALD, MD, MSC SONIA S. ANAND, MD, PHD and the use of the older fasting plasma 2,3,4 2,4,5 SALIM YUSUF, MD, DPHIL HERTZEL C. GERSTEIN, MD, MSC cutoff for of Ͼ7.8 4 PATRICK SHERIDAN, MSC FOR THE DREAM TRIAL INVESTIGATORS mmol/l (Ͼ140 mg/dl) rather than the cur- rent, more sensitive value of 7.0 mmol/l (126 mg/dl) (6). OBJECTIVE — The purpose of this study was to identify reproductive risk factors associated The prevalence of dysglycemia (type with dysglycemia (diabetes, impaired glucose tolerance, and ) in a 2 diabetes, impaired glucose tolerance contemporary multiethnic population. [IGT], and impaired fasting glucose [IFG]) is increasing; however, reproduc- RESEARCH DESIGN AND METHODS — We studied 14,661 women screened with an tive risk factors are often underrecognized. oral glucose tolerance test for the Diabetes Reduction Assessment with Ramipril and Rosiglita- In particular, their association with the zone Medication (DREAM) trial. Reproductive risk factors were compared in normoglycemic and dysglycemic women. more recently recognized forms of glucose dysregulation, IGT and IFG, have not yet RESULTS — Dysglycemia was significantly associated with the number of children born been well studied. The detection of dys- (odds ratio 1.03 per child [95% CI 1.01–1.05]), age (1.05 per year [1.04–1.05]), non-European glycemia could be improved if risk factors ancestry (1.09 [1.01–1.17]), preeclampsia/eclampsia (1.14 [1.02–1.27]), irregular periods (1.21 were better known. Moreover, if repro- [1.07–1.36]), and gestational diabetes mellitus (GDM) (1.53 [1.35–1.74]). The relationship ductive factors such as parity and pre- between GDM and dysglycemia did not differ across BMI tertiles (P ϭ 0.84) nor did the rela- eclampsia are risk factors for dysglycemia, tionships of other risk factors. they could be used to refine screening ap- proaches. The goal of this research was to CONCLUSIONS — Reproductive factors, particularly GDM, are associated with dysglyce- identify reproductive risk factors for dys- mia in middle-aged women from many ethnicities. Reproductive factors can be used to counsel young women about their future risk of dysglycemia, whereas in middle age they may help screen glycemia in a contemporary, multiethnic for dysglycemia. group of women.

Diabetes Care 31:1635–1638, 2008 RESEARCH DESIGN AND METHODS — This is a study of estational diabetes mellitus (GDM) ated with an increased risk of type 2 14,661 women screened as possible par- is a well-known reproductive risk diabetes, with an odds ratio (OR) of 1.16 ticipants in the Diabetes Reduction As- G factor for subsequent type 2 diabe- per pregnancy (95% CI 1.04–1.20) (3). sessment with Ramipril and Rosiglitazone tes (1). Other reproductive factors such as An even larger study comprising 2,310 Medication (DREAM) trial (7,8), a large, preeclampsia are associated with women with type 2 diabetes reported that international, multicenter, randomized, resistance during pregnancy and may also parity greater than six was associated with double-blind, controlled diabetes preven- increase the subsequent risk for diabetes. a relative risk (RR) of diabetes of 1.56 tion trial. Participants were volunteers Furthermore, some (2–4) but not all (5) (95% CI 1.27–1.91); however, the esti- recruited from 21 countries on five conti- studies suggest that pregnancy itself is a mate of the RR decreased to 1.19 (0.97– nents from a wide variety of sources in- risk factor for future type 2 diabetes. For 1.48) after adjustment for current age (2). cluding first-degree relatives of diabetic example, a population-based study of The applicability of these results is limited individuals in diabetes clinics, ads in 1,186 elderly women showed that, even by the homogeneity of the population newspapers, pharmacies, national diabe- after accounting for age, obesity, and fam- (registered nurses with relatively high so- tes associations, newsletters, clinics, com- ily history of diabetes, parity was associ- cioeconomic status and 98% Caucasian) munity announcements, screening programs, and targeted mailings. Institu- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● tional research ethics boards at each site From the 1Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, McMaster Uni- approved the DREAM trial. versity and Hamilton Health Sciences, Hamilton, Ontario, Canada; the 2Department of Medicine, Mc- 3 Master University and Hamilton Health Sciences, Hamilton, Ontario, Canada; the Division of Assessment Cardiology, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada; the 4Pop- ulation Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, On- After an overnight (8–18 h) fast, partici- tario, Canada; and the 5Division of Endocrinology and Metabolism, McMaster University and Hamilton pants consumed 75 g anhydrous glucose Health Sciences, Hamilton, Ontario, Canada. and provided fasting and 2-h blood sam- Corresponding author: Sarah D. McDonald, [email protected]. ples for local measurement of plasma glu- Received 27 March 2008 and accepted 27 April 2008. Published ahead of print at http://care.diabetesjournals.org on 5 May 2008. DOI: 10.2337/dc08-0621. cose. At the same time they completed a The funding organizations had no part in the design of the study; the collection, analysis, or interpretation 12-page questionnaire regarding baseline of the data; or the decision to approve publication of the finished manuscript. characteristics, medications, and personal © 2008 by the American Diabetes Association. Readers may use this article as long as the work is properly and family history, and women com- cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons. pleted a 1-page reproductive question- org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby naire regarding regularity of menstrual marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. cycles, fertility, how many children they

DIABETES CARE, VOLUME 31, NUMBER 8, AUGUST 2008 1635 Dysglycemia and reproductive risk factors

Table 1—Baseline characteristics of participants and age-adjusted univariate analyses of reproductive risk factors and the risk of dysglycemia

Age-adjusted No P value OR (95% CI) Dysglycemia dysglycemia (unadjusted) of dysglycemia n 6,298 8,363 Age (years) 55.1 Ϯ 11.1 50.0 Ϯ 10.0 Ͻ0.0001 NA Number of children 2.74 Ϯ 1.6 2.53 Ϯ 1.3 Ͻ0.0001 1.05 (1.04–1.06) Low socioeconomic states 2,243 (37.7) 2,636 (33.2) Ͻ0.0001 1.09 (1.01–1.17) Non-European ancestry 3,339 (53.0) 4,649 (55.6) 0.002 1.10 (1.02–1.17) Preeclampsia/eclampsia 700 (11.0) 853 (10.1) 0.10 1.19 (1.07–1.32) Irregular periods 608 (9.6) 734 (8.8) 0.08 1.22 (1.09–1.38) GDM 588 (9.4) 673 (8.1) 0.01 1.58 (1.40–1.78) Early menopause 124 (2.0) 217 (2.6) 0.01 1.24 (0.99–1.56) BMI (kg/m2) 31.6 Ϯ 6.0 29.4 Ϯ 6.0 Ͻ0.0001 1.06 (1.06–1.07) Data are means Ϯ SD and n (%) unless otherwise indicated. Dysglycemia indicates IFG, IGT, or type 2 diabetes, irregular periods indicates Յ6 menstrual cycles per year between the ages of 18 and 45 years not including pregnancy, and early menopause indicates permanent cessation of menses Ͻ45 years of age. NA, not applicable. had given birth to, and complications of for reproductive risk factors for dysglyce- 1.01–1.05]), age (1.05 per year [1.04– pregnancy including GDM, preeclamp- mia. Factors that were statistically signif- 1.05]), non-European ancestry (1.09 sia, or eclampsia. icant at P Ͻ 0.10 in the age-adjusted [1.01–1.17]), a history of preeclampsia/ analysis were included in the multivariate eclampsia (1.14 [1.02–1.27]), irregular Definitions logistic regression to determine their in- menses (1.21 [1.07–1.36]), and GDM Type 2 diabetes was defined as fasting dependent relationship with prevalent (1.53 [1.35–1.74]) (Fig. 1). Early meno- plasma glucose Ն7.0 mmol/l (Ն126 mg/ dysglycemia. This model was rerun for pause (1.24 [0.98–1.53]) and low socio- dl) or plasma glucose Ն11.1 mmol/l each tertile of BMI (and P values for het- economic status (0.95 [0.88–1.02]) were (Ն200 mg/dl) 2 h after a 75-g oral glucose erogeneity were calculated) to determine no longer significantly associated with load. IGT was defined as plasma glucose whether the risk of dysglycemia for each dysglycemia. 7.8–11.0 mmol/l (140–199 mg/dl) 2 h risk factor varied with BMI. All P values To determine whether there was an after a 75-g oral glucose load. IFG was are reported as two-tailed. All analyses interaction between BMI and the repro- defined as fasting glucose of 6.1–6.9 were performed using SAS software (ver- ductive risk factors, particularly GDM, we mmol/l (110–124 mg/dl). Dysglycemia sion 9.1; SAS Institute, Cary, NC). reran the multiple regression model for was defined as IFG, IGT, or type 2 diabe- each tertile of BMI, with 27.1 and 32.2 tes. Parity was defined as the number of RESULTS — Table 1 presents the base- defining lower, middle, and upper levels. infants a woman had borne. Irregular line characteristics of the women with (n ϭ The relationships between GDM and cur- menses was defined as six or fewer men- 6, 298) and without (n ϭ 8, 363) dysglyce- rent dysglycemia did not differ signifi- strual cycles per year between the ages of mia, whose 2-h plasma glucose concentra- cantly across tertiles of BMI (Pheterogeneity 18 and 45 years not including pregnancy tions were 10.0 Ϯ 3.1 versus 5.7 Ϯ 1.1 ϭ 0.84), nor for any of the other risk fac- Ͻ Ն and was used as a surrogate for polycystic mmol/l, respectively (P 0.0001), with tors (Pheterogeneity 0.10 for all). The ORs ovary syndrome. Early menopause was fasting values of 6.3 Ϯ 1.4 versus 5.0 Ϯ 1.1 for GDM and current dysglycemia for defined as the permanent cessation of mmol/l (P Ͻ 0.0001, respectively). Women each tertile of BMI (Ͻ27.1, 27.1–32.2, menstrual periods before age 45. Income with dysglycemia were significantly older and Ͼ32.2) were 1.81 [95% CI 1.42– range tables with five strata were devel- than those without dysglycemia (55.1 vs. 2.30], 1.44 [1.14–1.81], and 1.47 [1.20– oped specific to each country in which 50.0 years, respectively, P Ͻ 0.0001). After 1.81], respectively. recruitment occurred; low socioeconomic adjustment for age, most of the reproduc- status was defined as the lowest strata for tive factors remained significantly associ- CONCLUSIONS — This large, mul- that country. In Canada, for example, that ated with dysglycemia, including the tiethnic study of middle-aged women included a household income Յ$29,999 number of children a woman gave birth to showed that a history of GDM is indepen- and for the U.S. it was Յ$15,400. Non- (OR 1.05 per child [95% CI 1.04–1.06]), a dently associated with prevalent dysgly- European ancestry was defined as anyone history of preeclampsia/eclampsia (1.19 cemia, confirming that pregnancy is a indicating any ancestry other than Euro- [1.07–1.32]), irregular menses (1.2 [1.09– “stress test for life” (9,10). This observa- pean at the time of their clinic visit. 1.38]), GDM (1.58 [1.40–1.78]), low so- tion may be understood in light of the fact cioeconomic status (1.09 [1.01–1.17]), and that the occurrence of GDM is clear evi- Statistical analysis non-European ancestry (1.10 [1.02–1.17]) dence of an impaired ability to maintain Women were classified as those with and (Table 1). normoglycemia under the metabolic without dysglycemia. Continuous vari- In a multivariate model that included stress of pregnancy and is consistent with ables were compared using a t test, and age, ancestry, and fertility-related factors, previous reports (11–14) from smaller categorical variables were compared with dysglycemia was significantly associated studies. Hence, in young women of child- a ␹2 test. Logistic regression was used to with the number of children a woman bearing age, reproductive factors, partic- calculate age-adjusted ORs and 95% CI gave birth to (OR 1.03 per child [95% CI ularly GDM, can be used to counsel

1636 DIABETES CARE, VOLUME 31, NUMBER 8, AUGUST 2008 McDonald and Associates

dysglycemia was independently associ- ated with a history of several reproductive risk factors, particularly GDM. Moreover, the relationship between prior GDM and current dysglycemia persisted across BMI strata.

Acknowledgments— The DREAM Trial was funded by the Canadian Institutes of Health Research, sanofi-aventis, GlaxoSmithKline, and King Pharmaceuticals through the Univer- sity Industry Grant Program. S.Y. holds a Heart and Stroke Foundation Chair in Cardio- vascular Research. S.S.A. holds the Eli Lilly Canada–May Cohen Chair in Women’s Health. H.C.G. holds the Population Health Institute Chair in Diabetes Research spon- sored by aventis.

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